Omega-3 polyunsaturated fatty acid levels in the diet and in red blood cell membranes of depressed patients.Edwards R: University Department of Psychiatry, University of Sheffield, UK; Peet M, Shay J, Horrobin DJ Affect Disord 1998 Mar 48:149-55AbstractBACKGROUND: There is a hypothesis that lack of n-3 polyunsaturated fatty acids (PUFAs) is of aetiological importance in depression. Docosahexaenoic acid, a member of the n-3 PUFA family, is a crucial component of synaptic cell membranes. The aim of this study was to measure RBC membrane fatty acids in a group of depressed patients relative to a well matched healthy control group. METHOD: Red blood cell (RBC) membrane levels, and dietary PUFA intake were measured in 10 depressed patients and 14 matched healthy control subjects. RESULTS: There was a significant depletion of RBC membrane n-3 PUFAs in the depressed subjects which was not due to reduced calorie intake. Severity of depression correlated negatively with RBC membrane levels and with dietary intake of n-3 PUFAs. CONCLUSION: Lower RBC membrane n-3 PUFAs are associated with the severity of depression. LIMITATIONS: Although patient numbers were small, confounding factors were well controlled for and the results were highly significant. Results of the dietary data would tend to be weakened due to the limitations associated with dietary assessment. CLINICAL RELEVANCE: The findings raise the possibility that depressive symptoms may be alleviated by n-3 PUFA supplementation.

Arachidonic acid to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression.Adams PB: Central Region Mental Health Service, Rockhampton Base Hospital, Queensland, Australia; Lawson S, Sanigorski A, Sinclair AJLipids 1996 Mar 31 Suppl:S157-61AbstractIn this study of 20 moderately to severely depressed patients, diagnosed using current research diagnostic criteria and excluding known bipolar affective disorder and reactive depression, we investigated relationships between severity of depression and levels and ratios of n-3 and n-6 long-chain polyunsaturated fatty acids (PUFA) in plasma and erythrocyte phospholipids (PL). Severity of depression was measured using the 21-item Hamilton depression rating scale (HRS) and a second linear rating scale (LRS) of severity of depressive symptoms that omitted anxiety symptoms. There was a significant correlation between the ratio of erythrocyte PL arachidonic acid (AA) to eicosapentaenoic acid (EPA) and severity of depression as rated by the HRS (P < 0.05) and the LRS for depression (P < 0.01). There was also a significant negative correlation between erythrocyte EPA and the LRS (P < 0.05). The AA/EPA ratio in plasma PL and the ratio of erythrocyte long-chain (C20 and C22 carbon) n-6 to long-chain n-3 PUFA were also significantly correlated with the LRS (P < 0.05). These findings do not appear to be simply explained by differences in dietary intake of EPA. We cannot determine whether the high ratios of AA/EPA in both plasma and erythrocyte PL are the result of depression or whether tissue PUFA change predate the depressive symptoms. We suggest, however, that our findings provide a basis for studying the effect of the nutritional supplementation of depressed subjects, aimed at reducing the AA/EPA ratio in tissues and severity of depression.

Depletion of omega-3 fatty acid levels in red blood cell membranes of depressive patients.Peet M: University Department of Psychiatry, Sheffield, United Kingdom; , Murphy B, Shay J, Horrobin DBiol Psychiatry 1998 Mar 43:315-9AbstractBACKGROUND: It has been hypothesized that depletion of cell membrane n3 polyunsaturated fatty acids (PUFA), particularly docosahexanoic acid (DHA), may be of etiological importance in depression. METHODS: We measured the fatty acid composition of phospholipid in cell membranes from red blood cells (RBC) of 15 depressive patients and 15 healthy control subjects. RESULTS: Depressive patients showed significant depletions of total n3 PUFA and particularly DHA. Incubation of RBC from control subjects with hydrogen peroxide abolished all significant differences between patients and controls. CONCLUSIONS: These findings suggest that RBC membranes in depressive patients show evidence of oxidative damage. Possible interpretations, and implications for the etiology and treatment of depression, are discussed.

Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial.Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, Marangell LBArch Gen Psychiatry 1999 May 56:407-12Abstract BACKGROUND: Omega3 fatty acids may inhibit neuronal signal transduction pathways in a manner similar to that of lithium carbonate and valproate, 2 effective treatments for bipolar disorder. The present study was performed to examine whether omega3 fatty acids also exhibit mood-stabilizing properties in bipolar disorder. METHODS: A 4-month, double-blind, placebo-controlled study, comparing omega3 fatty acids (9.6 g/d) vs placebo (olive oil), in addition to usual treatment, in 30 patients with bipolar disorder. RESULTS: A Kaplan-Meier survival analysis of the cohort found that the omega3 fatty acid patient group had a significantly longer period of remission than the placebo group (P = .002; Mantel-Cox). In addition, for nearly every other outcome measure, the omega3 fatty acid group performed better than the placebo group. CONCLUSION: Omega3 fatty acids were well tolerated and improved the short-term course of illness in this preliminary study of patients with bipolar disorder.

Seafood consumption, the DHA content of mothers' milk and prevalence rates of postpartum depression: a cross-national, ecological analysis.Hibbeln JR: Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Park 5, Room 150, 12420 Parklawn Drive, Rockville, MD 20892, USAJ Affect Disord 2002 May 69:15-29AbstractBACKGROUND: Mothers selectively transfer docosahexaenoic acid (DHA) to their fetuses to support optimal neurological development during pregnancy. Without sufficient dietary intake, mothers become depleted of DHA and may increase their risk of suffering major depressive symptoms in the postpartum period. We postulated that the DHA content of mothers' milk and seafood consumption would both predict prevalence rates of postpartum depression across countries. METHODS: Published prevalence data for postpartum depression were included that used the Edinburgh Postpartum Depression Scale (n=14532 subjects in 41 studies). These data were compared to the DHA, eicosapentaenoic acid (EPA) and arachidonic acid (AA) content in mothers' milk and to seafood consumption rates in published reports from 23 countries. RESULTS: Higher concentrations of DHA in mothers' milk (r=-0.84, p<0.0001, n=16 countries) and greater seafood consumption (r=-0.81, p<0.0001, n=22 countries) both predicted lower prevalence rates of postpartum depression in simple and logarithmic models, respectively. The AA and EPA content of mothers' milk were unrelated to postpartum depression prevalence. LIMITATIONS: These findings do not prove that higher omega-3 status cause lower prevalence rates of postpartum depression. Data on potentially confounding factors were not uniformly available for all countries. CONCLUSIONS: Both lower DHA content in mothers' milk and lower seafood consumption were associated with higher rates of postpartum depression. These results do not appear to be an artifact of cross-national differences in well-established risk factors for postpartum depression. Interventional studies are needed to determine if omega-3 fatty acids can reduce major postpartum depressive symptoms.

A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia.Fenton WS: NIMH, NIH, Bethesda, MD 20892-9621, USA; Dickerson F, Boronow J, Hibbeln JR, Knable MAm J Psychiatry 2001 Dec 158:2071-4AbstractOBJECTIVE: This study determined if augmentation of neuroleptics with 3 g/day of ethyl eicosapentaenoic acid (EPA) improves symptoms and cognition in patients with schizophrenia or schizoaffective disorder. METHOD: Eighty-seven patients meeting criteria for schizophrenia or schizoaffective disorder who had residual symptoms despite neuroleptic treatment were randomly assigned to receive either 3 g/day of ethyl EPA (N=43) or placebo (N=44) in a 16-week, double-blind supplementation trial. Assessments were performed at baseline and at weeks 1, 2, 4, 8, 12, and 16; a cognitive battery was administered at baseline and at week 16. RESULTS: No differences were found between groups in positive or negative symptoms, mood, cognition, or global impression ratings. Results were similar for the intention-to-treat (N=87) and completer (N=75) groups. CONCLUSIONS: For schizophrenia patients treated with 3 g/day of ethyl EPA, improvement in residual symptoms and cognitive impairment was no greater than for schizophrenia patients treated with placebo.

Fish consumption and depressive symptoms in the general population in Finland.Tanskanen A: Department of Psychiatry, University of Kuopio, Finland; Hibbeln JR, Tuomilehto J, Uutela A, Haukkala A, ViinamÃ¤ki H, Lehtonen J, Vartiainen EPsychiatr Serv 2001 Apr 52:529-31AbstractFish contains high concentrations of omega-3 polyunsaturated fatty acids. Several studies have reported depletions of omega-3 fats among depressed patients, and a cross-national comparison has revealed a significant inverse correlation between annual prevalence of major depression and fish consumption. In a sample of 3,204 Finnish adults, depressive symptoms were estimated with the Beck Depression Inventory. A frequency question was used to measure fish consumption. Multiple logistic regression analysis was conducted to assess the association between depression and fish consumption. After the analysis adjusted for potential confounders, the likelihood of having depressive symptoms was significantly higher among infrequent fish consumers than among frequent consumers.

Plasma total cholesterol concentrations do not predict cerebrospinal fluid neurotransmitter metabolites: implications for the biophysical role of highly unsaturated fatty acids.Hibbeln JR: Laboratories of Membrane Biochemistry and Biophysics and Clinical Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20852, USA; Umhau JC, George DT, Shoaf SE, Linnoila M, Salem NAm J Clin Nutr 2000 Jan 71:331S-8SAbstractLow concentrations of a metabolite of serotonin found in cerebrospinal fluid (CSF), 5-hydroxyindolacetic acid (5-HIAA), are strongly associated with suicidal and violent behaviors. Although lowering of plasma total cholesterol has been suggested to increase mortality from suicide and violence by decreasing concentrations of CSF 5-HIAA via changes in membrane biophysical properties, highly unsaturated fatty acids may play a more important role. Violent and nonviolent comparison groups, early- and late-onset alcoholics, and healthy comparison subjects were studied to control for alcohol use and predisposition to violence. Fasting plasma total cholesterol and CSF were assayed under stringently controlled conditions. When all groups were combined (n = 234), plasma cholesterol concentrations had a weak positive correlation with CSF 5-HIAA (r = 0.18, P < 0.01). However, age correlated with both plasma total cholesterol and CSF 5-HIAA concentrations. When age was included in multiple regression models, the correlation between cholesterol and CSF 5-HIAA concentrations was not significant. Cholesterol correlated weakly with CSF 5-HIAA concentrations only in late-onset alcoholics after age was controlled for, but the relation was not significant after correction for multiple testing. CSF homovanillic acid did not correlate with plasma total cholesterol in any group. Plasma total cholesterol had no apparent relation to CSF neurotransmitter metabolites in any group of subjects. Highly unsaturated essential fatty acids, which are also critical determinants of membrane biophysical properties and may be linked to brain serotonin concentrations, should also be considered in studies examining the effect of lowering fat intake on the incidence of suicide and violence.

Fatty acid analysis of blood plasma of patients with Alzheimer's disease, other types of dementia, and cognitive impairment.Conquer JA: Department of Human Biology and Nutritional Sciences, University of Guelph, Ontario, Canada; Tierney MC, Zecevic J, Bettger WJ, Fisher RHLipids 2000 Dec 35:1305-12AbstractFatty acid differences, including docosahexaenoic acid (DHA; 22:6n-3) have been shown in the brains of Alzheimer's patients (AD) as compared with normal age-matched individuals. Furthermore, low serum DHA is a significant risk factor for the development of AD. The relative concentration of DHA and other fatty acids, however, in the plasma of AD patients compared with patients with other kinds of dementias (other dementias; OD), patients who are cognitively impaired but nondemented (CIND), or normal patients is not known. In this study we analyzed the total phospholipid, phosphatidylcholine (PC), phosphatidylethanolamine (PE), and lysophosphatidylcholine (lysoPC) fractions of plasma from patients diagnosed with AD, OD, or CIND and compared them with a group of elderly control subjects with normal cognitive functioning. Plasma phospholipid and PC levels of 20:5n-3, DHA, total n-3 fatty acids, and the n-3/n-6 ratio were lower in the AD, OD, and CIND groups. Plasma phospholipid 24:0 was lower in the AD, OD, and CIND groups as compared with the group of control patients, and total n-6 fatty acid levels were higher in the AD and CIND groups only. In the plasma PE fraction, levels of 20:5n-3, DHA, and the total n-3 fatty acid levels were significantly lower in the AD, OD, and CIND groups. DHA levels were lower in the lysoPC fraction of CIND individuals only. There were no other differences in the fatty acid compositions of the different phospholipid fractions. Therefore, in AD, OD, and CIND individuals, low levels of n-3 fatty acids in the plasma may be a risk factor for cognitive impairment and/or dementia. Interestingly, a decreased level of plasma DHA was not limited to the AD patients but appears to be common in cognitive impairment with aging.

Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia.Peet M: Academic Department of Psychiatry, Northern General Hospital, The Longley Centre, Sheffield, UK; Brind J, Ramchand CN, Shah S, Vankar GKSchizophr Res 2001 Apr 49:243-51AbstractEvidence that the metabolism of phospholipids and polyunsaturated fatty acids (PUFA) is abnormal in schizophrenia provided the rationale for intervention studies using PUFA supplementation. An initial open label study indicating efficacy for n-3 PUFA in schizophrenia led to two small double-blind pilot studies. The first study was designed to distinguish between the possible effects of two different n-3 PUFA: eicosapentaenoic acid (EPA) and docohexaenoic acid (DHA). Forty-five schizophrenic patients on stable antipsychotic medication who were still symptomatic were treated with either EPA, DHA or placebo for 3 months. Improvement on EPA measured by the Positive and Negative Syndrome Scale (PANSS) was statistically superior to both DHA and placebo using changes in percentage scores on the total PANSS. EPA was significantly superior to DHA for positive symptoms using ANOVA for repeated measures. In the second placebo-controlled study, EPA was used as a sole treatment, though the use of antipsychotic drugs was still permitted if this was clinically imperative. By the end of the study, all 12 patients on placebo, but only eight out of 14 patients on EPA, were taking antipsychotic drugs. Despite this, patients taking EPA had significantly lower scores on the PANSS rating scale by the end of the study. It is concluded that EPA may represent a new treatment approach to schizophrenia, and this requires investigation by large-scale placebo-controlled trials.

Randomized, placebo-controlled study of ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia.Emsley R, Myburgh C, Oosthuizen P, van Rensburg SJAm J Psychiatry 2002 Sep 159:1596-8AbstractOBJECTIVE: The study investigated the efficacy and tolerability of ethyl-eicosapentaenoic acid (E-EPA) as add-on treatment in chronic, severe schizophrenia. METHOD: A randomized, parallel-group, double-blind, placebo-controlled, fixed-dose, add-on study was conducted over 12 weeks. Forty patients with persistent symptoms after at least 6 months of stable antipsychotic treatment received E-EPA or placebo, in addition to their existing treatment. RESULTS: At 12 weeks, the E-EPA group had significantly greater reduction of Positive and Negative Syndrome Scale total scores and of dyskinesia scores than the placebo group. CONCLUSIONS: EPA may be an effective and well-tolerated add-on treatment in schizophrenia.

Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder.Nemets B: Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheva, Israel; Stahl Z, Belmaker RHAm J Psychiatry 2002 Mar 159:477-9AbstractOBJECTIVE: Studies have reported that countries with high rates of fish oil consumption have low rates of depressive disorder. The authors studied a specific omega-3 fatty acid, the ethyl ester of eicosapentaenoic acid (E-EPA), as an adjunct to treatment for depressive episodes occurring in patients with recurrent unipolar depressive disorder who were receiving maintenance antidepressant therapy. METHOD: Twenty patients with a current diagnosis of major depressive disorder participated in a 4-week, parallel-group, double-blind addition of either placebo or E-EPA to ongoing antidepressant therapy. Seventeen of the patients were women, and three were men. RESULTS: Highly significant benefits of the addition of the omega-3 fatty acid compared with placebo were found by week 3 of treatment. CONCLUSIONS: It is not possible to distinguish whether E-EPA augments antidepressant action in the manner of lithium or has independent antidepressant properties of its own.